Racemization of optically active 2-substituted phenyl glycine esters

ABSTRACT

A process for preparing racemic mixtures containing nearly equal amounts of stereo isomers of compounds of formula (I), or their salts, by heating an enantiomerically enriched material with thionyl chloride.  
                 
 
     A required useful enantiomer may thereby be recovered from unwanted mother liquors that would otherwise be otherwise be discarded.

BACKGROUND TO THE INVENTION FIELD OF THE INVENTION

[0001] The present invention pertains to a process for the recovery ofenantiomers from unwanted mother liquors using racemic mixturescontaining stereoisomers having the structure (I) below, or its salt, byheating an enantiomerically enriched chemical mixture with thionylchloride.

[0002] The present invention is also directed to a process for preparingracemic mixtures containing nearly equal amounts of enantiomers of2-chlorophenyl glycine methyl ester from mother liquors enriched withunwanted isomers, as its hydrochloride salt, by heating the motherliquors with thionyl chloride.

DISCUSSION OF RELATED ART

[0003] Racemization is generally carried out by heating an acid with orwithout the presence of an alkali or a solvent. Free amino acids aredifficult to racemize. The temperature required for racemization isoften in the range of 140°-180° C. and some decomposition occurs attemperatures within this high range.

[0004] Decomposition is extensive with 2-(2-chlorophenyl) glycine, notonly because it is difficult to racemize, but also because it easilydegrades. 2-(2-chlorophenyl) glycine is an intermediate required in itsenantiomerically pure (S) enantiomer for the production of methylalpha-5 (4,5,6,7-tetrahydro (3,2,-c) thienopyridyl)(2chlorophenyl)-acetate) to produce an important active pharmaceuticalingredient known as clopidogrel. The enantiomerically pure form of2(2-chlorophenyl) glycine is derived from its racemic mixture by opticalresolution separation techniques.

[0005] The fact that single isomer chiral molecules are known toracemize and revert to optically inactive racemic molecules underadverse conditions is well known in the art. Chemistry and Biochemistryof the Amino Acids, edited by G. C. Barret Chapman and Hall, ChapterThirteen, deals in some detail with the subject of racemization of aminoacids.

[0006] U.S. Pat. No. 4,713,470 (the “'470 patent”) describesracemization of amino acids carried out by using specially preparedpolymers. The racemization process described in the '470 patent uses anaromatic aldehyde polymer synthesized by reacting an hydroxylaromaticaldehyde with a chloromethylated vinylbenzene polymer under reactiveconditions to form an aromatic aldehyde polymer wherein the aldehydicmoiety is linked to the polymer through an ether linkage. There is alsodisclosed a process for the production of the racemization catalyst usedtherein.

[0007] U.S. Pat. No. 4,647,692 (the “'692 patent”) is directed to aprocess for racemization of amino acids by using ketones and organicacids such as acetic acid. Specifically, the '692 patent discusses aprocess for resolution of free α-amino acids with in situ racemization.The resolution of 4-hydroxyphenylglycine and 3,4-dihydroxy-phenylglycinewith 3-bromocamphor-9-sulphonic acid with in situ racemization isspecifically mentioned.

[0008] U.S. Pat. No. 4,638,086 (the “086 patent”) covers a process forracemization of optically active amino acids that comprises heatingamino acids with an effective amount of benzoic or phenylacetic acid ortheir derivatives which are monosubstituted or polysubstituted on thenucleus by identical or different substituents selected from the groupconsisting of halogen, lower alkyl, lower alkoxy, hydroxy, acyloxy, andnitro.

[0009] U.S. Pat. No. 4,237,313 (the “'313 patent”) is directed to aprocess for the racemization of optically active phenylacetic acidderivatives. The process comprises heating an optically activephenylacetic acid derivative to a temperature of at least 150° C. in thepresence or absence of an inert solvent. None of the above-referencedpatents are directed to a process for the recovery of enantiomers fromunwanted mother liquors using racemic mixtures containing stereoisomersof compounds having the general structure (I).

[0010] Compounds obtained by reacting esters of 2chlorophenylglycinewith thienopyridine are useful in the treatment of cardiac conditionsand may also be used as anti-platelet agents. U.S. Pat. No. 4,847,265refers to the (S)+enantiomer of clopidogrel. Other patents such as U.S.Pat. Nos. 4,529,596 and 5,204,469, also refer tomethylalpha-5(4,5,6,7-tetrahydro(3,2-c)thienopyridyl)(2chlorophenyl)-acetate,its isomers and its methods of preparation. U.S. Pat. No. 6,180,793refers to this compound and also to methods of preparing the requiredintermediates. These patents refer to the chemical synthesis of racemic(S)(+) or (R)(−) clopidogrel by various methods. In some instances, theresulting clopidogrel is resolved in the end, while in other instances,the resolution step is carried during an intermediate stage.

[0011] In each of the aforementioned patents mentioned in the aboveparagraph, half of the material produced is typically discarded as theunwanted isomer. It may be either in one of the intermediate stages orin the final stage of clopidogrel. For example, the '793 patent coverssynthesis of clopidogrel wherein the resolution step is carried out inany of four different stages in the progression of the synthesis. In anyof these steps, the unwanted isomer, representing approximately 50% ofthe quantity produced, is discarded. Discarding of this material isexpensive and contributes to total production cost. It also forms aneffluent and increases effluent treatment costs. From an economicviewpoint, it is wasteful to discard an otherwise useful enantiomer froman enantiomerically enriched mixture, such as mother liquors withunwanted isomers. It is preferable to convert these mother liquors intothe desired enantiomers via racemization techniques followed byseparation of the desired isomer using optical resolution, therebyrecovering the required enantiomer from what would otherwise be wastedmaterial.

SUMMARY OF THE INVENTION

[0012] One aspect of the present invention pertains to a process for therecovery of enantiomers from racemic mixtures containing stereoisomersof compounds having the general formula (I) below

[0013] or its salt by heating an enantiomerically enriched chemicalmixture with thionyl chloride.

[0014] Another aspect of the present invention includes:

[0015] a. Liberating 2-chlorophenyl glycine methyl ester as free basefrom a concentrated (R)-enantiomer enriched mother liquor, whichcontains the tartarate or D-camphorsulfonate salt of an unwantedenantiomer;

[0016] b. Heating the free base with thionyl chloride so as to effectracemization to form racemized ester hydrochloride;

[0017] c. Isolating the racemized ester hydrochloride; and

[0018] d. Liberating a racemized ester from the isolated, racemizedester hydrochloride as a further free base from its hydrochloride salt.

[0019] The racemized ester may be further processed by conventionalresolution steps well known in the art. The present invention thusoffers the advantage of recovering a desired enantiomer from unwantedmother liquors that would be otherwise discarded. It further provides anenvironmental advantage in that chemical waste is reduced.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention relates to a racemization process forre-use of 2-(2-chlorophenyl) glycine from an enantiomerically enrichedmixture. The methyl ester of racemic 2-(2-chlorophenyl) glycine isresolved using either D-camphor sulfonic acid or tartaric acid.Generally tartaric acid or D-camphorsulfonic acid is added to a solutionof 2-chlorophenylglycine in a suitable solvent such as methanol. Oncooling, the required enantiomer precipitates out as a D-camphorsulfonate salt or as a tartarate salt.

[0021] The mother liquor contains the solvent and the D-camphorsulfonate or tartarate salt of the 2-(2-chlorophenyl) glycine methylester. According to the process covered by the present invention it canbe further processed. The mother liquor is first concentrated byremoving the solvent under reduced pressure. The concentrated motherliquor of tartarate generally exhibits an optical rotation

[α]_(D) ²⁰ between −8520 and +5°, C=1 in methanol.

[0022] The concentrated liquors are then treated with an alkali,preferably sodium hydroxide to liberate the 2-(2-chlorophenyl) glycinemethyl ester as its base.

[0023] The base solution obtained from the above-step is dissolved inapproximately ten times the volume of methanol. An equimolar amount ofthionyl chloride is added to this solution and the mixture is heatedbetween 30° C. and 90° C. for a period ranging between 2 hrs to 20 hrs,preferably 8 to 12 hrs. At the end of this period, the specific opticalrotation of the resulting mixture is nearly zero which indicatessuccessful racemization.

[0024] The racemized solution contains the 2-(2-chlorophenyl)glycinemethyl ester as the hydrochloride. This solution is treated with analkali preferably sodium hydroxide solution to liberate the racemizedester. This material is now ready for processing into clopidogrelfollowing any of the techniques described in the patents referred topreviously.

[0025] It should be appreciated that this process allows for therecovery and recyclability of a substantial portion of the startingmaterial in the synthesis of clopidogrel. This result providessubstantial monetary savings and reduces environmental waste.

[0026] While the following examples specifically describe this process,the invention should not be limited by what is described below but onlyby the claims.

[0027] The following examples further describe the present invention.

EXAMPLE 1

[0028] Liberation of free (−) enriched 2-(2-chlorophenyl) glycine methylester free base from its tartaric acid salt:

[0029] To (−) enriched methyl 2-(2-chlorophenyl) glycinate(+)tartaricacid salt of methyl 2-chlorophenyl glycinate, 90 Kg present in 30 litersmethanol, 450 liters of 10% sodium bicarbonate solution (45 Kg of sodiumbicarbonate dissolved in 450 lits of water) is added slowly whilestirring keeping the temperature of the reaction mixture between 25°C.-30° C., until a pH of the solution is in the range of 7.0-7.5(checked by means of pH meter.) Thereafter, stirring is discontinued andthe reaction mixture is allowed to settle. The bottom layer of methyl2-(2-chlorophenyl) glycinate is separated and fifty liters ofdichloromethane is charged for the extraction of the upper aqueouslayer. The reaction mixture is stirred for 15 minutes, and then thelayers are allowed to separate. The lower dichloromethane extract isremoved and combined with the methyl 2-(2-chlorophenyl) glycinate layer.This mixture is dried over anhydrous sodium sulfate (5 Kg) anddichloromethane distilled at atmospheric pressure.

[0030] Yield: −45 to 50 Kg.

Specific Optical Rotation (SOR)(hydrochloride)[α]_(D) ²⁰ −85° to 5°(c=1% in methanol)

EXAMPLE 2

[0031] Racemization of methyl 2-chlorophenyl glycinate and isolation ofliberated racemized ester as free base.

[0032] One hundred kilograms of methyl 2-(2-chlorophenyl glycinate (SOR−85° to +5°) is dissolved in three hundred fifty liters (350 liters) ofmethanol in a 1000 liter Mild Steel glass lined reactor. This mixture iscooled to 5° C. by circulating chilled water or brine through anexternal jacket.

[0033] Forty five liters (73.7 kilograms) of thionyl chloride are addedto the reaction mixture while stirring and maintaining a temperature ofthe reaction mixture between 25° C. and 30° C. After completion of theaddition, water or brine circulation is stopped and heating of thereaction mixture begins by means of hot water circulation through anexternal jacket. Heating is continued and reflux is maintained for abouttwelve hours.

[0034] The methanol is now slowly distilled out while maintainingreduced pressure so as to maintain the temperature of the reactionmixture below 60° C. Distillation is continued until three hundredliters of methanol is distilled out. The reaction mixture is then cooledto 25° C.-30° C. and five hundred liters (500 liters) of water is addedto the reaction mixture while stirring. Stirring is continued until aclear solution is obtained. The reaction mixture is then cooled to 10°C. 47% caustic lye is added slowly, while maintaining stirring, until apH between 7.0 and 7.5 of the reaction mixture is obtained.

[0035] Stirring and cooling are then stopped and the reaction mixture isallowed to settle. The organic layer is separated as(±)-methyl-2-(2-chlorophenyl) glycinate.

[0036] Yield: −75-80 kilogramsSOR(hydrochloride)  [α]_(D)²⁰ = −5  to  +5^(∘)  (c = 1%  in  methanol)

[0037] The racemized ester solution is now ready for resolution as permethods available in prior art. In an analogous manner, the unwantedenantiomers of 2-(2-bromophenyl)-glycine and 2-(2-methoxyphenyl)glycinemay also be racemized and recovered.

EXAMPLE 3

[0038] Conversion of methyl 2-(2-chlorophenyl) glycinate to its tartaricacid salt.

[0039] 60 kilograms of (+) tartaric acid (SOR=12° c=20, H₂O ) isdissolved in three hundred fifty liters of methanol in a mild steelglass lined reactor. Methyl 2-(2-chlorophenyl) glycinate obtained by theprevious procedure (eighty kilograms) is dissolved in fifty liters ofmethanol and added to the reaction mixture at once. The reaction mixtureis stirred for approximately five minutes and transferred to a highdensity polyethylene tank. Five grams of pure tartaric acid salt ofmethyl 2-(2-chlorophenyl) glycinate(SOR=˜90°) is added as seed. Thereaction mass is kept at room temperature for ninety six hours.

[0040] Crystals of (+) tartaric acid salt of methyl-2-(2chlorophenyl)glycinate and separated by centrifugation and dried at 40° C. for eighthours

[0041] Yield: −49-50 kilogramsSpecific  optical  rotation  [α]_(D)²⁰ = 85^(∘)   − 93^(∘)  (c = 1%  in  methanol)  

EXAMPLE 4

[0042] Isolation of Second Crop:

[0043] The mother liquor of example 3 is transferred to a reactor andthe methanol is distilled out under reduced pressure while maintainingthe temperature below 60° C. After recovery of approximately 250 litersof methanol, the reaction mass is collected in polyethylene drums andallowed to solidify. The solid mass containing hemitartarate of(−)-methyl 2-(2-chlorophenyl) glycinate as a major product is stored assecond crop for future reprocessing. Yield: About 100-120 kg.SOR  after  drying  at  60^(∘)  C.  [α]_(D)²⁰ = −85^(∘)    to  +5^(∘)  (c = 1%  in  methanol)  

EXAMPLE 5

[0044] Isolation of methyl-2-(2-chlorophenyl) glycinate from second cropgenerated after resolution.

[0045] The second crop obtained after resolution (SOR=−85° to +5°degrees) is dissolved in 700 liters of water. 40% caustic lye is addeduntil a pH between 7.0-7.5. is obtained. Once the pH range is attained,stirring is stopped and the reaction mass is allowed to settle. A lowerlayer of methyl 2-chlorophenyl glycinate is separated and 50 liters ofdichloromethane is added to the reactor and stirred for 15 minutes. Alower dichloromethane layer is separated and combined with the productand dried over anhydrous sodium sulphate. Dichloromethane is thenrecovered under reduced pressure keeping the temperature within therange 25° C.-30° C. degrees.

[0046] Yield: 40-45 Kg. (SOR as HCl=−85° to +5°; c=1% in methanol)

[0047] Methyl-2-(2-chlorophenyl) glycinate obtained by above procedureis racemized, resolved and converted to (+) methyl-2-(2chlorophenyl)glycinate as per examples 1 and 2.

EXAMPLE 6

[0048] Isolation of Resolved Ester from Tartarate

[0049] The (+)-methyl-2-(2-chlorophenyl) glycinate (+)tartaric acid saltof methyl-2-(2-chlorophenyl) glycinate obtained in Example-3 above(fifty kilograms) is dissolved in two hundred liters (200 liters) ofwater in a clean stainless steel reactor. 10% sodium bicarbonatesolution is added while stirring keeping the temperature of the reactionmixture between 25° C.-30° C., until a pH of the solution is within therange of 7.0-7.5 (checked by means of pH meter.) Upon attaining thepreferred pH stirring is stopped and the reaction mixture is allowed tosettle. A layer of methyl-2-(2-chlorophenyl) glycinate is separated andfifty liters of dichloromethane is charged for the extraction of theupper aqueous layer. This is stirred for 15 minutes and then stoppedallowing the layers to separate. The lower dichloromethane extract layeris separated and combined with (+)-methyl-2-(2-chlorophenyl) glycinate.This mixture is dried over anhydrous sodium sulfate (5 Kg) anddichloromethane recovered under vacuum keeping the temperature between25-30° C. Yield: −27.5 Kg.SOR(hydrochloride)  [α]_(D)²⁰ = +114  to  +115°  (c = 1%  in  methanol)

What is claimed is:
 1. A process for preparing a racemic mixturecontaining substantially equimolecular amounts of enantiomers of thecompound represented by structure (I):


2. A process as in claim 1, further comprising racemizing one of an (R)enantiomer and an (S) enantiomer of the compound.
 3. The process ofclaim 1 wherein the racemization is carried out by heating with thionylchloride.
 4. The process of claim 1 wherein the mixture contains unequalquantities of (R) and (S) isomers of the compound.
 5. The process as inclaim 4, wherein the racemization is carried out by heating with thionylchloride at a temperature approximately within the range of 40° C. and90° C.
 6. A process of racemization to recover enantiomers from unwantedmother liquors, comprising: (a) liberating 2-(2-chlorophenyl) glycinatemethyl ester as a free base from a concentrated R-enantiomer enrichedmother liquor, that contains at least one of a tartarate orD-camphorsulfonate salt of an unwanted enantiomer; and (b) heating thefree base with thionyl chloride so as to effect racemization to formracemized ester hydrochloride.
 7. The process as in claim 6, whereinstep (b) is carried out at a temperature within the range of about 40°C. and about 90° C.
 8. The process as in claim 7, further comprising:(a) isolating the racemized ester hydrochloride; and (b) liberating aracemized ester, as a free base, from the isolated, racemized esterhydrochloride.
 9. A process for preparing a racemic mixture containingsubstantially equimolecular amounts of enantiomers of the compoundrepresented by the structure (I) below or a salt thereof:

wherein preparation of the racemic mixture is carried out by heating anoptically active mixture with thionyl chloride to effect racemization.10. A process as in claim 9, wherein the heating is performed at atemperature between about 40° C. and about 90° C.
 11. A process ofracemization of an optically active mixture of compounds comprising thesteps of: (a) breaking up a tartarate mixture so as to obtain asubstantially pure free amino ester; and (b) contacting thesubstantially pure free ester with thionyl chloride so as to effectracemization.
 12. A process as in claim 11, wherein the racemization iscarried out by heating a solution containing the racemic mixture withthionyl chloride at a temperature within the range of about 40° C. andabout 90° C.
 13. The process of liberating free (−) enriched2-(2-chlorophenyl) glycine methyl ester free base from its tartaric acidsalt comprising the steps of: (a) providing (−) enrichedmethyl-2-(2-chlorophenyl) glycinate (+) tartaric acid salt ofmethyl-2-(2-chlorophenyl) glycinate in methanol; (b) addingapproximately 10% sodium bicarbonate solution until a pH approximatelywithin the range of 7.0-7.50 is attained; (c) allowing the reactionmixture to settle; (d) separating a bottom layer ofmethyl-2-(2-chlorophenyl) glycinate from the solution in step (c); (e)extracting an upper aqueous layer of the solution of step (c) withdichloromethane; (f) removing the dichloromethane layer of step (e) andcombining said dichloromethane layer with the methyl-2(2-chlorophenyl)glycinate layer; and (g) drying the mixed layers of step (f) overanhydrous sodium sulfate and dichloromethane distillation at atmospherictemperature.
 14. The process of claim 13 wherein step (b) is essentiallyperformed while keeping the temperature of the methanol solutionapproximately between 25° C.-30° C.
 15. The process of racemization ofmethyl-2-(2-chlorophenyl) glycinate comprising the steps of: (a)providing a solution of methyl-2-(2-chlorophenyl) glycinate dissolved inmethanol; (b) cooling the mixture of step (a) to approximately 5° C. bychilling with at least one of a circulating water or a brine; (c) addingthionyl chloride to the cooled mixture of step (b) while maintaining atemperature of the mixture between approximately 25° C. and 30° C.; (d)heating the mixture of step (c); (e) distilling out the methanol fromthe heated mixture of step (d) while maintaining a temperature of themixture below approximately 60° C.; (f) cooling the reaction mixture ofstep (e); (g) adding water to the mixture of step (f) while stirringuntil a substantially clear solution is obtained; (h) cooling themixture of step (g) to approximately 10° C.; (i) adding an approximate47% solution of caustic to the mixture of step (g) until a pH betweenapproximate 7.0-7.5 is obtained; and (j) allowing the mixture of step(i) to settle and separating (±)-methyl-2-(2-chlorophenyl) glycinate.16. The process of converting methyl-2-(2-chlorophenyl) glycinate to atartaric acid salt of methyl-2-(2-chlorophenyl) glycinate comprising thesteps of: (a) dissolving tartaric acid in methanol; (b) dissolvingmethyl-2-(2-chlorophenyl) glycinate in methanol; (c) adding the mixtureof step (b) to the mixture of step (a); (d) stirring the mixture of step(c); (e) adding tartaric acid salt of methyl-2-(2-chlorophenyl)glycinate to seed the mixture of step (d); and (f) separating thesolution of step (e) into crystals of tartaric acid salt ofmethyl-2-(2-chlorophenyl) glycinate and a mother liquor.
 17. The processof synthesizing hemitartate of (−)-methyl-2-(2chlorophenyl) glycinatecomprising the steps of: (a) distilling out the methanol from the motherliquor obtained in step (f) of claim 16; (b) collecting the reactionmass of step (a); and (c) allowing the reaction mass to settle.
 18. Theprocess of isolating (−)-methyl-2-(2-chlorophenyl) glycinate comprisingthe steps of: (a) Providing a solid mass containing a hemitartate ofmethyl-2-(2-chlorophenyl) glycinate; (b) dissolving the mass of step (a)in water; (c) adding approximately 40% caustic lye to the solution ofstep (b) until a pH approximately within the range of 7.0-7.5 isobtained; (d) allowing the mixture of step (c) to settle; (e) separatinga layer of methyl-2-(2-chlorophenyl) glycinate from the mixture of step(d) to yield a reactive solution; (f) adding dichloromethane to thereactive solution of step (e); (g) separating a lower dichloromethanelayer from the mixture of step (f) to yield a reactive product; (h)combining the separated dichloromethane layer of step (g) with thereactive product of step (e); and (i) drying the product of step (h)over anhydrous sodium sulfate and dichloromethane distillation atatmospheric pressure.
 19. The process of isolating a resolved estercomprising the steps of: (a) dissolving a (+) tartaric acid salt ofmethyl 2chlorophenyl glycinate in water; (b) adding approximately 10%sodium bicarbonate solution to the solution of step (a) until a pHwithin the range of 7.0-7.5 is obtained; (c) allowing the mixture ofstep (b) to settle; (d) separating a layer of methyl-2-(2-chlorophenyl)glycinate and charging the aqueous layer of step (c) with an effectiveamount of dichloromethane; (e) stirring the aqueous layer of step (d)after charging dichloromethane; (f) separating a dichloromethane extractlayer from the solution of step (e); (g) combining the dichloromethaneextract layer of step (f) with (+)-methyl-2-(2-chlorophenyl) glycinateto yield a mixture; (h) drying the mixture of step (g) over anhydroussodium sulfate; and (i) recovering dichloromethane under vacuum.